Drugs for the treatment of depression have been available for over 30 years. Both the first monoamino oxidase inhibitor (MAO inhibitor), iproniazide, and the first tricyclic antidepressant (T.ACA), imipramine, were placed on the market at the end of the 50's. The second generation antidepressants represent a considerable improvement on the traditional tricyclic antidepressants, or on the irreversible unspecific MAO inhibitors. In spite of this, they still offer side effects, and what is more important, the latency time until the therapeutic effect appears is still too long for the treatment to be deemed optimal.
The latest class of antidepressants placed on the market was the one comprising the selective serotonin reuptake inhibitors, outstanding among which are fluoxetine (Lilly ES433720), paroxetine (Ferrosan, ES422734) and sertraline (Pfizer, ES496443). The products of this class have a high degree of structural diversity in comparison with other types of serotonin reuptake inhibitors, such as may be the tricyclic antidepressants. In spite of their structural variety, these compounds are highly selective for the serotonin receptor. In fact, their binding to .alpha. and .beta. adrenergic, dopaminergic., histamine and muscarine receptors is insignificant. It is postulated that this could be due to a great structural similarity to the pharmacophore, which is responsible for their specificity, and relative affinity to the corresponding serotonin receptor.
Among the most frequent adverse effects of the serotonin reuptake inhibitors are those related with gastrointestinal disorders. The majority of them also cause inhibition of the hepatic metabolism of other drugs with the corresponding pharmaco-dynamic interactions and have a retarded onset of their antidepressive action.
With this background in mind, there arises the need to continue investigating so as to create a third generation of antidepressants. The four points that an antidepressant must fulfil to be considered as a member of the third generation are:
1. Faster action
2. Broader efficacy
3. Less side effects
4. Safer in case of overdose
The first of these four points is the one offering the greatest challenge in antidepressant research since the harm that it represents for a depression patient that the drug does not start to show its effects until the elapse of several weeks after the start of the treatment is obvious.
The reason why the ailment takes time to remit, after treatment with monoamine reuptake inhibitors, appears to be due to a process of desensitisation of the presynaptic 5-HT.sub.1A receptors, which means that the serotoninergic tone is reduced until this desensitisation has occurred.
It may be gathered from all the above that an antidepressive treatment which, further to inhibiting the serotonin reuptake, were to involve a blocking or a rapid desensitisation of the 5-HT.sub.1A somatodentritic autoreceptors would increase the antidepressive effectiveness, on allowing the serotonin concentration in the serotoninergic terminations to rise quickly. In this sense, there has been proposed the simultaneous administration of serotonin reuptake inhibitors with selective 5-HT.sub.1A receptor antagonists, such as pindolol (Artigas F. et al., Arch. Gen. Psychiatry, 51, 248-251 (1994); Blier P. et al., J. Clin. Pharmacol. 15, 217-222 (1995)) to facilitate the quickest possible onset of the antidepressive effect. This theory has led the researchers suggest that the addition of products blocking the 5-HT.sub.1A type autoreceptors may prevent the onset of this negative feedback system and potentiate the effect of the serotonin reuptake inhibitors.
One Lilly patent (EP 0 687 472) claims the potentiation of the effect of the serotonin reuptake inhibitors by increasing the availability of certain brain neurotransmitters (serotonin among them) by combining the serotonin reuptake inhibitors with selective 5-HT.sub.1A receptor antagonists.
Bearing the above background in mind, it is therefore an object of this invention to synthesise compounds having this dual activity, i.e., serotonin reuptake inhibitors with affinity for the 5-HT.sub.1A receptor.
The invention relates in particular to the synthesis and pharmacological activity of new benzothiophene derivatives of the general formula (1).
Products to some extent similar to those disclosed here have been claimed in the literature. Thus, for example, U.S. Pat. No. 2,979,507 claims products having the general formula: ##STR3##
To be precise, there are disclosed the products: ##STR4##
where R may be H or 2-OCH.sub.3 among others.
The document EP 0 596 120 claims products of the general formula: ##STR5##
where X is generally: --S, or S(O)-- but may be, among others: --C(O)--; --CH(OR)--; --C(N--OR)--; --CH(NH.sub.2 --; A may be an alkylene group and T is generally a 1,2-benzoisoxazole or 1,2-benzothiazole ring, but may be any other aromatic ring. Nevertheless, the above document does not contemplate the possibility of R.sub.1 and R.sub.2 jointly forming a ring, whereby the products claimed do not include benzothiophenes.
The document GB 1096341 discloses products of the general formula ##STR6##
where R may be: --CH.sub.2 --CH.sub.2 --C(O)--Ar and Ar may be, among others, a thiophene ring, although not a benzothiophene ring.
To be precise, the above patent describes the products: ##STR7##
where R.sub.1 is 2-F or 4-F or 4-Cl.
U.S. Pat. No. 3,002,976 claims compounds of the general formula: ##STR8##
where R is H, methyl or halogen.
The documents WO 9616052 and WO 9615792, describe products of general formula: ##STR9##
where Z is N or CH, and Ar.sup.1 may be a benzothiophene ring. In these compounds the aromatic ring (Ar.sup.2) is not directly attached to the piperazine ring, but through a spacer X (CH.sub.2, CO, etc.), unlike the compounds of the present invention.
The document DE 2360545 describes piperazines including the compound: ##STR10##
benzothiophene which, like the above named compounds, does not have the aromatic ring directly attached to the piperazine.